Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases

ABSTRACT

The present invention relates to certain 1-substituted-2,3,4,5-tetrahydro-3-benzazepine derivatives of Formula (I), that are modulators of the 5HT2C receptor. Accordingly, compounds of the present invention are useful for the prophylaxis or treatment of 5HT2C receptor associated diseases, conditions or disorders, such as, obesity and related disorders.

This application is related to U.S. Provisional Patent Application, Ser.No. 60/479,280, which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to certainsubstituted-2,3,4,5-tetrahydro-3-benzazepine derivatives that aremodulators of the 5HT_(2C) receptor. Accordingly, compounds of thepresent invention are useful for the prophylaxis or treatment of5HT_(2C) receptor associated diseases, conditions or disorders, such as,obesity and related disorders.

BACKGROUND OF THE INVENTION

Obesity is a life-threatening disorder in which there is an increasedrisk of morbidity and mortality arising from concomitant diseases suchas, but not limited to, type II diabetes, hypertension, stroke, certainforms of cancers and gallbladder disease.

Obesity has become a major healthcare issue in the Western World andincreasingly in some third world countries. The increase in the numberof obese people is due largely to the increasing preference for high fatcontent foods but also, and this can be a more important factor, thedecrease in activity in most people's lives. In the last 10 years therehas been a 30% increase in the incidence of obesity in the USA and thatabout 30% of the population of the USA is now considered obese. In spiteof the growing awareness of the health concerns linked to obesity thepercentage of individuals that are overweight or obese continue toincrease. In fact, the percentage of children and adolescents who aredefined as overweight has more than doubled since the early 1970s andabout 13 percent of children and adolescents are now seriouslyoverweight. The most significant concern, from a public healthperspective, is that children who are overweight grow up to beoverweight or obese adults, and accordingly are at greater risk formajor health problems. Therefore, it appears that the number ofindividuals that are overweight or obese will continue to increase.

Whether someone is classified as overweight or obese is generallydetermined on the basis of his or her body mass index (BMI) which iscalculated by dividing their body weight (kilograms—Kg) by their heightsquared (meters squared—m²). Thus, the units for BMI are Kg/m². The BMIis more highly correlated with body fat than any other indicator ofheight and weight. A person is considered overweight when they have aBMI in the range of 25-30 kg/m². Whereas a person with a BMI over 30kg/m² is classified as obese and obesity is further divided into threeclasses, Class I (BMI of about 30 to about 34.9 kg/m²), Class II (BMI ofabout 35 to 39.9 kg/m²) and Class III (about 40 kg/m² or greater); seeTABLE 1 below for complete classifications. TABLE 1 CLASSIFICATION OFWEIGHT BY BODY MASS INDEX (BMI) BMI CLASSIFICATION <18.5 Underweight18.5-24.9 Normal 25.0-29.9 Overweight 30.0-34.9 Obesity (Class I)35.0-39.9 Obesity (Class II) >40 Extreme Obesity (Class III)As the BMI increases for an individual there is an increased risk ofmorbidity and mortality relative to an individual with normal BMI.Accordingly, overweight and obese individuals (BMI of about 25 kg/m² andabove) are at increased risk for physical ailments such as, but notlimited to, high blood pressure, cardiovascular disease (particularlyhypertension), high blood cholesterol, dyslipidemia, type II(non-insulin dependent) diabetes, insulin resistance, glucoseintolerance, hyperinsulinemnia, coronary heart disease, angina pectoris,congestive heart failure, stroke, gallstones, cholescystitis andcholelithiasis, gout, osteoarthritis, obstructive sleep apnea andrespiratory problems, some types of cancer (such as endometrial, breast,prostate, and colon), complications of pregnancy, poor femalereproductive health (such as menstrual irregularities, infertility,irregular ovulation), diseases of reproduction (such as sexualdysfunction, both male and female, including male erectile dysfunction),bladder control problems (such as stress incontinence), uric acidnephrolithiasis, psychological disorders (such as depression, eatingdisorders, distorted body image, and low self esteem). Research hasshown that even a modest reduction in body weight can correspond to asignificant reduction in the risk of developing other ailments, such as,but not limited to, coronary heart disease.

As mentioned above, obesity increases the risk of developingcardiovascular diseases. Coronary insufficiency, atheromatous disease,and cardiac insufficiency are at the forefront of the cardiovascularcomplications induced by obesity. The incidence of coronary diseases isdoubled in subjects less than 50 years of age who are 30% overweight.The diabetes patient faces a 30% reduced lifespan. After age 45, peoplewith diabetes are about three times more likely than people withoutdiabetes to have significant heart disease and up to five times morelikely to have a stroke. These findings emphasize the inter-relationsbetween risks factors for NIDDM and coronary heart disease and thepotential value of an integrated approach to the prevention of theseconditions based on the prevention of obesity [Perry, I. J., et al. BMJ310, 560-564 (1995)]. It is estimated that if the entire population hadan ideal weight, the risk of coronary insufficiency would decrease by25% and the risk of cardiac insufficiency and of cerebral vascularaccidents by 35%.

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina andincreases the risk of cataracts and glaucoma. Finally, diabetes isassociated with nerve damage, especially in the legs and feet, whichinterferes with the ability to sense pain and contributes to seriousinfections. Taken together, diabetes complications are one of thenation's leading causes of death.

The first line of treatment for individuals that are overweight or obeseis to offer diet and life style advice, such as, reducing the fatcontent of their diet and increasing their physical activity. Howevermany patients find these difficult to maintain and need additional helpfrom drug therapy to sustain results from these efforts.

Most currently marketed products have been unsuccessful as treatmentsfor obesity owing to a lack of efficacy or unacceptable side-effectprofiles. The most successful drug so far was the indirectly acting5-hydroxytryptamine (5-HT) agonist d-fenfluramine (Redux™) but reportsof cardiac valve defects in up to one third of the patient populationled to its withdrawal by the FDA in 1998.

In addition, two drugs have recently been launched in the USA andEurope: Orlistat (Xenical™), a drug that prevents absorption of fat bythe inhibition of pancreatic lipase, and Sibutramine (Reductil™), a5-HT/noradrenaline re-uptake inhibitor. However, side effects associatedwith these products may limit their long-term utility. Treatment withXenical™ is reported to induce gastrointestinal distress in somepatients, while Sibutramine has been associated with raised bloodpressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in numerousphysiological processes both in health and in psychiatric disorders.5-HT has been implicated in the regulation of feeding behavior for sometime. 5-HT works by inducing a feeling of fullness or satiety so eatingstops earlier and fewer calories are consumed. It has been shown that astimulatory action of 5-HT on the 5HT_(2C) receptor plays an importantrole in the control of eating and in the anti-obesity effect ofd-fenfluramine. As the 5HT_(2C) receptor is expressed in high density inthe brain (notably in the limbic structures, extrapyramidal pathways,thalamus and hypothalamus i.e. PVN and DMH, and predominantly in thechoroid plexus) and is expressed in low density or is absent inperipheral tissues, a selective 5HT_(2C) receptor agonist can be aneffective and safe anti-obesity agent. Also, 5HT_(2C) knockout mice areoverweight with cognitive impairment and susceptibility to seizure thusestablishing the clear use for a 5HT_(2C) receptor agonist in 5HT_(2C)receptor associated diseases or disorders.

The 5HT_(2C) receptor plays a role in obsessive compulsive disorder,some forms of depression, and epilepsy. Accordingly, 5HT_(2C) receptoragonists can have anti-panic properties, and properties useful for thetreatment of sexual dysfunction. In addition, 5HT_(2C) receptor agonistsare useful for the treatment of psychiatric symptoms and behaviors inindividuals with eating disorders such as, but not limited to, anorexianervosa and bulimia nervosa. Individuals with anorexia nervosa oftendemonstrate social isolation. Anorexic individuals often presentsymptoms of being depressed, anxious, obsession, perfectionistic traits,and rigid cognitive styles as well as sexual disinterest. Other eatingdisorders include, anorexia nervosa, bulimia nervosa, binge eatingdisorder (compulsive eating) and ED-NOS (i.e., eating disorders nototherwise specified—an official diagnosis). An individual diagnosed withED-NOS possess atypical eating disorders including situations in whichthe individual meets all but a few of the criteria for a particulardiagnosis. What the individual is doing with regard to food and weightis neither normal nor healthy.

In addition, the 5HT_(2C) receptor is also involved in other diseases,conditions and disorders; such as Alzheimer Disease (AD). Therapeuticagents currently prescribed for Alzheimer's disease (AD) arecholinomimetic agents that act by inhibiting the enzymeacetylcholinesterase. The resulting effect is increased levels ofacetylcholine, which modestly improves neuronal function and cognitionin patients with AD. Although, dysfunction of cholinergic brain neuronsis an early manifestation of AD, attempts to slow the progression of thedisease with these agents have had only modest success, perhaps becausethe doses that can be administered are limited by peripheral cholinergicside effects, such as tremors, nausea, vomiting, and dry mouth. Inaddition, as AD progresses, these agents tend to lose theireffectiveness due to continued cholinergic neuronal loss.

Therefore, there is a need for agents that have beneficial effects inAD, particularly in alleviating symptoms by improving cognition andslowing or inhibiting disease progression, without the side effectsobserved with current therapies. Therefore, serotonin 5HT_(2C)receptors, which are exclusively expressed in brain, are attractivetargets.

A major feature of AD is the formation of senile plaques made of amyloiddeposits in a selected area of the brain. New therapies should focus onprevention of the production of these senile plaques. An amyloid depositcomposed mainly of beta-amyloid peptide (Aβ) occupies the plaque center.Aβ is a peptide of 40 to 43 residues derived from a larger amyloidprecursor protein, APP [Selkoe D J, et al. Ann Rev Neurosci, 1994,17:489-517]. APP is a ubiquitous transmembrane glycoprotein that ispresent at high levels in brain cells. APP also exists as secretedforms. By cleavage in the Aβ region of APP, the long N-terminal fragment(secreted APP, APPs) is secreted into the extracellular space. The rateof Aβ production appears to be inversely coupled to rate APPs secretion.In several cell cultures, APPs secretion was accompanied by reductionsin secreted Aβ [Buxbaum J D, et al. Proc Nat Acad Sci, 1993,90:9195-9198; Gabuzda D, et al. J Neurochem, 1993, 61:2326-2329; Hung AY, et al. J Biol Chem, 1993, 268:22959-22962; and Wolf B A, et al. JBiol Chem, 1995, 270:4916-4922], suggesting that stimulated secretoryprocessing of APP into secreted APPs is associated with reducedformation of potentially amyloidogenic derivatives, or plaques.

APPs is found in plasma and cerebrospinal fluid [Ghiso J, et al. BiochemBiophys Res Comm, 1989, 163:430-437; and Podlisny M B, et al. BiochemBiophys Res Commun, 1990, 167:1094-1101]. Considering the abundance ofboth membrane-bound APP and APPs, they are likely to have significantbiological functions. Current knowledge about APP functions indicatesAPP is critically required for the maintenance of neuronal and synapticstructure and function. Membrane-bound APP has been suggested to have areceptor-like structure [Kang J, et al. Nature, 1987, 325:733-736], withthe cytoplasmic domain capable of complexing with a GTP-binding protein[Nishimoto I., et al. Nature, 1993, 362:75-79]. Membrane-embeddedfull-length APP might also have a cell adhesion function [Qiu W., et al.J Neurosci, 1995, 15:2157-2167].

APPs has been shown to be neurotrophic and neuroprotective in vitro[Mattson M P, et al. Neuron, 1993, 10:243-254; and Qiu W., et al. JNeurosci, 1995, 15:2157-2167]. Other proposed functions for APPs includethe regulation of blood coagulation [Cole G M, et al. Biochem BiophysRes Commun, 1990, 170:288-295; Smith R P, et al. Science, 1990,248:1126-1128; and Van Nostrand et al. Science, 1990, 248:745-748],wound-healing [Cunningham J M, et al. Histochemistry, 1991, 95:513-517],extracellular protease activity [Oltersdorf T, et al. Nature (London),1989, 341:144-147; and Van Nostrand W E, et al. Nature, 1989,341:546-548], neurite extension [Jin L., et al. J Neurosci, 1994,14:5461-5470; and Robakis N K, et al. in Molecular Biology ofAlzheimer's Disease. (T. Miyatake, D. J. Selkoe and Y. Ihara, ed.),1990, pp. 179-188, Elsevier Science Publishers B.V., Amsterdam], celladhesiveness [Schubert D, et al. Neuron, 1989, 3:689-694], cell growth,[Bhasin R., et al. Proc Natl Acad Sci USA, 1991, 88:10307-10311; andSaitoh T., Cell, 1989, 58:615-622], and differentiation [Araki W., etal. Biochem Biophys Res Commun, 1991, 181:265-271; Milward E A, et al.Neuron, 1991, 9:129-137; and Yamamoto K, et al. J Neurobiol, 1994,25:585-594].

The non-selective serotonin 5HT_(2C) agonist dexnorfenfluramine (DEXNOR)stimulated amyloid precursor protein (APPs) secretion in guinea pigswhile reducing levels of Aβ production in vivo following repeatadministration [Arjona A, et al. “Effect of a 5HT_(2C) serotoninagonist, dexnorfenfluramine, on amyloid precursor protein metabolism inguinea pigs,” Brain Res, 2002, 951:135-140]. Guinea pigs were chosenbecause guinea pig and human APP exhibit 98% sequence homology [Beck M,et al. Biochem Biophys Acta, 1997, 1351:17-21], the proteins areprocessed similarly [Beck M., et al. Neuroscience, 1999, 95:243-254],and the Aβ peptide sequences are identical [Johnstone E M, et al. BrainRes Mol Brain Res, 1991, 10:299-305]. Although DEXNOR is non-selective,the observed effects were attenuated by a selective serotonin 5HT_(2C)antagonist, while a selective serotonin HT_(2A) antagonist did notreverse the DEXNOR effects, indicating the serotonin 5HT_(2C) receptorsare the most relevant target for this effect.

In addition, 5-HT stimulates APPs ectodomain secretion via the serotonin5HT_(2A) and 5HT_(2C) receptors [Nitsch R M, et al. J Biol Chem, 1996,271(8):4188-4194]. In this study, researchers stimulated 3T3 fibroblastswith serotonin (5-HT), which were stably expressing serotonin 5HT_(2A)or 5HT_(2C) receptors. 5-HT increased APPs secretion in a dose-dependentmanner in both cell lines. Maximal stimulation of APPs secretion peakedat about 4-fold. Selective serotonin 5HT_(2A) and 5HT_(2C) antagonistsblocked the effects in each cell line.

A serotonin 5HT_(2C) receptor agonist can be effective for treating ADand preventing senile plaques. Support for this claim comes from thefact that Aβ is known to be neurotoxic and a key component in senileplaques involved in AD, APPs secretion and Aβ levels seem to beinversely related, and serotonin 5HT_(2C) agonists increase levels ofAPPs in vitro in cell lines stably expressing serotonin 5HT_(2C)receptors while in vivo serotonin 5HT_(2C) agonists increase levels ofAPPs and decrease levels of Aβ as measured in cerebral spinal fluid ofguinea pigs.

Evidence exists supporting the use of a compound of the presentinvention with agonist activity at the serotonin 5HT_(2C) receptor forthe treatment of AD. The compound of the invention can be used alone orin combination with another agent or agents (such as but not limited toAChE inhibitors) that are typically prescribed for AD.

Another disease, disorder or condition that can is associated with thefunction of the 5HT_(2C) receptor is erectile dysfunction (ED). Erectiledysfunction is the inability to achieve or maintain an erectionsufficiently rigid for intercourse, ejaculation, or both. An estimated20-30 million men in the United States have this condition at some timein their lives. The prevalence of the condition increases with age. Fivepercent of men 40 years of age report ED. This rate increases to between15% and 25% by the age of 65, and to 55% in men over the age of 75years.

Erectile dysfunction can result from a number of distinct problems.These include loss of desire or libido, the inability to maintain anerection, premature ejaculation, lack of emission, and inability toachieve an orgasm. Frequently, more than one of these problems presentsthemselves simultaneously. The conditions may be secondary to otherdisease states (typically chronic conditions), the result of specificdisorders of the urogenital system or endocrine system, secondary totreatment with pharmacological agents (e.g. antihypertensive drugs,antidepressant drugs, antipsychotic drugs, etc.) or the result ofpsychiatric problems. Erectile dysfunction, when organic, is primarilydue to vascular irregularities associated with atherosclerosis,diabetes, and hypertension.

There is evidence for use of a serotonin 5HT_(2C) agonist for thetreatment of sexual dysfunction in males and females. The serotonin5HT_(2C) receptor is involved with the processing and integration ofsensory information, regulation of central monoaminergic systems, andmodulation of neuroendocrine responses, anxiety, feeding behavior, andcerebrospinal fluid production [Tecott, L. H., et al. Nature 374:542-546 (1995)]. In addition, the serotonin 5HT_(2C) receptor has beenimplicated in the mediation of penile erections in rats, monkeys, andhumans.

The exact mechanism by which 5HT_(2C) receptors mediate penile erectionsremains unknown. However, there is good evidence, indirect and direct,supporting the role of serotonin 5HT_(2C) receptors in the mediation ofpenile erections. Anatomical studies have shown that the penis receivesautonomic innervation from sympathetic and parasympathetic nucleilocated in the spinal cord [Pescatori E S, et al. J Urol 1993; 149:627-32]. In agreement, experimental and clinical data support thatpenile erections are controlled by a spinal reflex. A closer analysisshowed that activation of 5HT₂ spinal receptors facilitated pudendalreflex in anesthetized cats [Danuser H and Thor K B, Br J Pharmacol1996; 118: 150-4]. Accordingly, stimulation of 5HT_(2C) receptors hasbeen shown to be proerectile [Millan M J, et al. European Journal ofPharmacology 1997; 325], and 5HT_(2C) receptors have been described onproerectile spinal parasympathetic neurons [Bancila M et al.Neuroscience 1999; 92: 1523-37].

Indirect evidence comes from the research and reports of the sideeffects induced by the use of selective serotonin reuptake inhibitors(SSRIs). SSRIs have demonstrated antagonist action at the serotonin5HT_(2C) receptors [Jenck et al. European Journal of Pharmacology 231:223-229 (1993); Lightlowler et al. European Journal of Pharmacology 296:137-43 (1996); and Palvimaki, E., et al. Psychopharmacology 126: 234-240(1996)]. Among the most derogatory side effects of SSRIs noted in humansis increased difficulty in attaining penile erection. Although SSRIshave a rich pharmacological profile, it is believed that the antagonisteffects of SSRIs at the 5HT_(2C) receptors could be implicated in theinhibition of penile erections [Palvimaki, E., et al. Psychopharmacology126: 234-240 (1996)].

Further evidence comes from studies with a variety compounds with knownagonist activity for the serotonin 5HT_(2C) receptor. Pharmacologicstudies with rats and rhesus monkeys provide direct evidence of theproerectile properties of agonist of the serotonin 5-HT_(2C) receptor[Millan M J, et al. European Journal of Pharmacology 1997; 325; andPomerantz, et al. European Journal of Pharmacology 243:227-34 (1993)].These pro-erectile effects were unaffected by antagonists for theserotonin 5HT_(2A) and 5HT_(2B) receptors, respectively. Antagonists ofthe serotonin 5HT_(2C) receptors attenuated the proerectile effects ofthe 5-HT_(2C) agonists. The inhibition action corresponded to eachantagonist's affinity for the 5-HT_(2C) receptors. In addition, agonistsof the serotonin 5HT_(2A) and 5HT_(2B) receptors did not elicit penileerections.

In summary, the 5HT_(2C) receptor is a validated and well-acceptedreceptor target for the prophylaxis and/or treatment of 5HT_(2C)mediated receptor diseases and disorders, such as, obesity, eatingdisorders, psychiatric disorders, Alzheimer Disease, sexual dysfunctionand disorders related thereto. It can be seen that there exists a needfor selective 5HT_(2C) receptor agonists that can safely address theseneeds. The present invention is directed to these, as well as other,important ends.

SUMMARY OF THE INVENTION

The present invention is drawn to compounds which bind to and modulatethe activity of the 5HT_(2C) receptor, and uses thereof. The term5HT_(2C) receptor as used herein includes the human sequences found inGeneBank accession number AF498983, naturally-occurring allelicvariants, mammalian orthologs, and recombinant mutants thereof.

One aspect of the present invention pertains to certainsubstituted-2,3,4,5-tetrahydro-3-benzazepine derivatives as representedby Formula (I):

wherein:

-   -   R₁ is H or C₁₋₈ alkyl;    -   R₂ is C₁₋₄ alkyl, —CH₂—O—C₁₋₄ alkyl, C₁₋₄ haloalkyl or CH₂OH;        and    -   R₃, R₄, R₅ and R₆ are each independently H, C₁₋₄ alkyl, amino,        cyano, halogen, C₁₋₄ haloalkyl, nitro or OH; or    -   a pharmaceutically acceptable salt, hydrate and solvate thereof;    -   provided that when R₂ is C₁₋₄ alkyl, —CH₂—O—C₁₋₄ alkyl, and        CH₂OH then R₃ and R₆ are not both hydrogen.

Some embodiments of the present invention are compounds of Formula (I)wherein the compounds are the R enantiomers.

Some embodiments of the present invention are compounds of Formula (I)wherein the compounds are the S enantiomers.

Another aspect of the present invention also pertains to pharmaceuticalcompositions comprising one or more compounds of the invention, and oneor more pharmaceutically acceptable carriers.

Another aspect of the present invention pertains to methods ofmodulating a 5HT_(2C) receptor comprising contacting said receptor witha therapeutically effective amount or dose of a compound as describedherein. Preferably, compounds of the present invention are agonists ofthe 5HT_(2C) receptor.

Another aspect of the present invention pertains to methods ofprophylaxis or treatment of disorders of the central nervous system;damage to the central nervous system; cardiovascular disorders;gastrointestinal disorders; diabetes insipidus or sleep apnea comprisingadministering to an individual in need of such prophylaxis or treatmenta therapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof.

Another aspect of the present invention pertains to methods ofdecreasing food intake of an individual comprising administering to saidindividual a therapeutically effective amount or dose of a compound ofthe present invention or a pharmaceutical composition thereof.

Another aspect of the present invention pertains to methods of inducingsatiety in an individual comprising administering to said individual atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof.

Another aspect of the present invention pertains to methods ofcontrolling weight gain of an individual comprising administering tosaid individual suffering from weight control a therapeuticallyeffective amount or dose of a compound of the present invention or apharmaceutical composition thereof.

Another aspect of the present invention pertains to methods of producinga pharmaceutical composition comprising admixing at least one compoundof the present invention and at least one pharmaceutically acceptablecarrier.

Another aspect of the present invention pertains to compounds, asdescribed herein, for use in a method of treatment of the human oranimal body by therapy.

Another aspect of the present invention pertains to compounds, asdescribed herein, for use in a method of prophylaxis or treatment ofdisorders of the central nervous system; damage to the central nervoussystem; cardiovascular disorders; gastrointestinal disorders; diabetesinsipidus or sleep apnea of the human or animal body by therapy.

Another aspect of the present invention pertains to use of compounds, asdescribed herein, for the manufacture of a medicament for use in thetreatment or prophylaxis of disorders of the central nervous system;damage to the central nervous system; cardiovascular disorders;gastrointestinal disorders; diabetes insipidus or sleep apnea.

In some embodiments, the disorders of the central nervous system areselected the group consisting of depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, Alzheimer disease, age-related behavioraldisorders, behavioral disorders associated with dementia, organic mentaldisorders, mental disorders in childhood, aggressivity, age-relatedmemory disorders, chronic fatigue syndrome, drug and alcohol addiction,obesity, bulimia, anorexia nervosa and premenstrual tension. In furtherembodiments, the disorder of the central nervous system is obesity. Infurther embodiments, the disorder of the central nervous system isAlzheimer disease. In further embodiments, the sexual dysfunction isMale erectile dysfunction.

In some embodiments, the damage to the central nervous system is bytrauma, stroke, neurodegenerative diseases, toxic CNS diseases orinfective CNS diseases. In further embodiments, the damage to thecentral nervous system is by encephalitis or meningitis.

In some embodiments, the cardiovascular disorder is thrombosis.

In some embodiments, the gastrointestinal disorder is dysfunction ofgastrointestinal motility.

In some embodiments, the invention pertains to methods for alleviationof a symptom of any of the diseases, conditions or disorders mentionedherein.

In some embodiments, the individual is a mammal.

In some embodiments, the individual is a mammal and preferably, themammal is a human.

In further embodiments, the human has a body mass index of about 18.5 toabout 45.

In further embodiments, the human has a body mass index of about 25 toabout 45.

In further embodiments, the human has a body mass index of about 30 toabout 45.

In further embodiments, the human has a body mass index of about 35 toabout 45.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

Agonists shall mean moieties that interact and activate the receptor,such as the 5HT_(2c) receptor and initiates a physiological orpharmacological response characteristic of that receptor. For example,when moieties activate the intracellular response upon binding to thereceptor, or enhance GTP binding to membranes.

The term ANTAGONISTS is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

Chemical Group, Moiety or Radical:

-   -   As used herein, the term “alkyl” is intended to denote        hydrocarbon compounds including straight chain, branched and        cyclic hydrocarbons, including for example but not limited to        methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl,        sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, n-pentyl,        isopentyl, tert-pentyl, cyclopentyl, cyclopentylmethyl, n-hexyl,        cyclohexyl, and the like. The term “C₁₋₈ alkyl” refers to an        alkyl group containing 1 to 8 carbon atoms. Likewise, the term        “C₁₋₄ alkyl” refers to an alkyl group containing 1 to 4 carbon        atoms. Throughout this specification, it should be understood        that the term alkyl is intended to encompass both non-cyclic        hydrocarbon compounds and cyclic hydrocarbon compounds. In some        embodiments of the compounds of the invention, alkyl groups are        non-cyclic. In further embodiments, alkyl groups are cyclic, and        in further embodiments, alkyl groups are both cyclic and        noncyclic. Where no preference is specified, the term “alkyl” is        intended to denote groups are both cyclic and non-cyclic.    -   The term “amino” denotes the group —NH₂.    -   The term “cyano” denotes the group —CN.    -   The term “C₁₋₄ haloalkyl” denotes an alkyl group; defined        herein, wherein the alkyl is substituted with one halogen up to        fully substituted and a fully substituted C₁₋₄ haloalkyl can        therefore be represented by the formula C_(n)L_(2n+1) wherein L        is a halogen; when more than one halogen is present then they        may be the same or different and selected from the group        consisting of F, Cl, Br or I. Examples of C₁₋₄ haloalkyl groups        include: fluoromethyl, difluoromethyl, trifluoromethyl,        chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and        the like.    -   The term “halogen” or “halo” denotes to a fluoro, chloro, bromo        or iodo group.    -   The term “nitro” refers to the group —NO₂.

Composition shall mean a material comprising at least two compounds ortwo components; for example, and not limitation, a PharmaceuticalComposition is a Composition.

Contact or Contacting shall mean bringing the indicated moietiestogether, whether in an in vitro system or an in vivo system. Thus,“contacting” a 5HT_(2C) receptor with a compound of the inventionincludes the administration of a compound of the present invention to anindividual, preferably a human, having a 5HT_(2C) receptor, as well as,for example, introducing a compound of the invention into a samplecontaining a cellular or more purified preparation containing a 5HT_(2C)receptor.

In Need of Prophylaxis or Treatment as used herein refers to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, etc. inthe case of humans; veterinarian in the case of animals, includingnon-human mammals) that an individual or animal requires or will benefitfrom prophylaxis or treatment. This judgment is made based on a varietyof factors that are in the realm of a caregiver's expertise, but thatincludes the knowledge that the individual or animal is ill, or will beill, as the result of a disease, condition or disorder that is treatableby the compounds of the invention. In general, “in need of prophylaxis”refers to the judgment made by the caregiver that the individual willbecome ill. In this context, the compounds of the invention are used ina protective or preventive manner. However, “in need of treatment”refers to the judgment of the caregiver that the individual is alreadyill, therefore, the compounds of the present invention are used toalleviate, inhibit or ameliorate the disease, condition or disorder.

Individual as used herein refers to any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

Pharmaceutical Composition shall mean a composition comprising at leastone active ingredient, whereby the composition is amenable toinvestigation for a specified, efficacious outcome in a mammal (forexample, and not limitation, a human). Those of ordinary skill in theart will understand and appreciate the techniques appropriate fordetermining whether an active ingredient has a desired efficaciousoutcome based upon the needs of the artisan.

Therapeutically Effective Amount as used herein refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Compounds of the Present Invention

One aspect of the present invention pertains to certainsubstituted-2,3,4,5-tetrahydro-3-benzazepine derivatives as representedby Formula (I):

wherein:

-   -   R₁ is H or C₁₋₈ alkyl;    -   R₂ is C₁₋₄ alkyl, —CH₂—O—C₁₋₄ alkyl, C₁₋₄ haloalkyl or CH₂OH;        and    -   R₃, R₄, R₅ and R₆ are each independently H, C₁₋₄ alkyl, amino,        cyano, halogen, C₁₋₄ haloalkyl, nitro or OH; or    -   a pharmaceutically acceptable salt, hydrate and solvate thereof;    -   provided that when R₂ is C₁₋₄ alkyl, —CH₂—O—C₁₋₄ alkyl, and        CH₂OH then R₃ and R₆ are not both hydrogen.

In some embodiments, when R₁ is H and R₂ is CH₃ then R₃, R₄ and R₆ cannot all be hydrogens and R₅ can not be hydrogen or iso-propyl.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

It is understood and appreciated that compounds of Formula (I) may haveone or more chiral centers, and therefore can exist as enantiomersand/or diastereomers. The invention is understood to extend to andembrace all such enantiomers, diastereomers and mixtures thereof,including but not limited to racemates. Accordingly, one embodiment ofthe present invention pertains to compounds of Formula (I) and formulaeused throughout this disclosure that are R enantiomers. Further, oneembodiment of the present invention pertains to compounds of Formula (I)and formulae used throughout this disclosure that are S enantiomers. Itis understood that compounds of Formula (I) and formulae used throughoutthis disclosure are intended to represent all individual enantiomers andmixtures thereof, unless stated or shown otherwise.

In some embodiments of the present invention are compounds of Formula(I) wherein R₁ is H. In some embodiments, compounds can be representedby Formula (Ia) as illustrated below:

wherein each variable in Formula (Ia) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention are compounds of Formula (I)wherein R₁ is C₁₋₈ alkyl. In some embodiments R₁ is methyl. In someembodiments, compounds can be represented by Formula (Ib) as illustratedbelow:

wherein each variable in Formula (Ib) has the same meaning as describedherein, supra and infra.

In some embodiments R₁ is ethyl. In some embodiments R₁ is n-propyl. Insome embodiments R₁ is iso-propyl. In some embodiments R₁ is n-butyl.

Some embodiments of the present invention are compounds of Formula (I)wherein R₂ is C₁₋₄ alkyl. In some embodiments R₂ is methyl. In someembodiments, compounds can be represented by Formula (Ic) as illustratedbelow:

wherein each variable in Formula (Ic) has the same meaning as describedherein, supra and infra.

In further embodiments R₂ is ethyl. In some embodiments R₂ isiso-propyl. In some embodiments R₂ is n-butyl.

Some embodiments of the present invention are compounds of Formula (I)wherein R₂ is C₁₋₄ haloalkyl. Examples of a C₁₋₄ haloalkyl groupinclude, but are not limited to, CH₂F, CHF₂, CF₃, CH₂CHF₂, CH₂CH₂F,CH₂CF₃ and CF₂CF₃. In some embodiments R₂ is —CF₃.

Some embodiments of the present invention are compounds of Formula (I)wherein R₃ is H. In some embodiments R₃ is C₁₋₄ alkyl. In someembodiments R₃ is methyl (i.e., —CH₃).

Some embodiments of the present invention are compounds of Formula (I)wherein R₃ is amino.

Some embodiments of the present invention are compounds of Formula (I)wherein R₃ is cyano.

Some embodiments of the present invention are compounds of Formula (I)wherein R₃ is halogen. In some embodiments R₃ is a fluorine atom. Insome embodiments, compounds can be represented by Formula (Ie) asillustrated below:

wherein each variable in Formula (Ie) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (Ie) and R₂ is C₁₋₄ alkyl; in furtherembodiments, R₂ is CH₃.

In some embodiments, R₃ is a chlorine atom. In some embodiments,compounds can be represented by Formula (Ig) as illustrated below:

wherein each variable in Formula (Ig) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (Ig) and R₂ is C₁₋₄ alkyl; in furtherembodiments, R₂ is CH₃.

In some embodiments R₃ is a bromine atom.

In some embodiments R₃ is an iodine atom.

Some embodiments of the present invention are compounds of Formula (I)wherein R₃ is C₁₋₄ haloalkyl. In some embodiments R₃ is CF₃.

Some embodiments of the present invention are compounds of Formula (I)wherein R₃ is nitro.

Some embodiments of the present invention are compounds of Formula (I)wherein R₃ is —OH.

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is H.

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is C₁₋₄ alkyl. In some embodiments, R₄ is methyl (i.e.,—CH₃).

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is amino.

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is cyano.

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is halogen. In some embodiments R₄ is a fluorine atom. Insome embodiments, compounds can be represented by Formula (Ii) asillustrated below:

wherein each variable in Formula (Ii) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (Ii) and R₂ is C₁₋₄ alkyl; in furtherembodiments, R₂ is CH₃.

In some embodiments R₄ is a chlorine atom. In some embodiments,compounds can be represented by Formula (Ik) as illustrated below:

wherein each variable in Formula (Ik) has the same meaning as describedherein, supra and infra. In some embodiments, some embodiments of thepresent are of Formula (Ik) and R₂ is C₁₋₄ alkyl; in furtherembodiments, R₂ is CH₃.

In some embodiments R₄ is a bromine atom.

In some embodiments R₄ is an iodine atom.

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is C₁₋₄ haloalkyl. In some embodiments R₄ is CF₃.

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is nitro.

Some embodiments of the present invention are compounds of Formula (I)wherein R₄ is —OH.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is H.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is C₁₋₄ alkyl. In some embodiments R₅ is methyl (i.e., —CH₃).

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is amino.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is cyano.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is halogen. In some embodiments R₅ is a fluorine atom. Insome embodiments, compounds can be represented by Formula (Im) asillustrated below:

wherein each variable in Formula (Im) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (Im) and R₂ is C₁₋₄ alkyl; in furtherembodiments, R₂ is CH₃.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is halogen. In some embodiments R₅ is a chlorine atom. Insome embodiments, compounds can be represented by Formula (Io) asillustrated below:

wherein each variable in Formula (Io) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (Io) and R₂ is C₁₋₄ alkyl; in furtherembodiments R₂ is CH₃.

In some embodiments R₅ is a bromine atom. In some embodiments R₅ is aniodine atom.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is C₁₋₄ haloalkyl. In some embodiments R₅ is CF₃.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is nitro.

Some embodiments of the present invention are compounds of Formula (I)wherein R₅ is —OH

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is H.

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is C₁₋₄ alkyl. In some embodiments R₆ is —CH₃.

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is amino.

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is cyano.

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is halogen. In some embodiments R₆ is a fluorine atom. Insome embodiments, compounds can be represented by Formula (Iq) asillustrated below:

wherein each variable in Formula (Iq) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (Iq) and R₂ is C₁₋₄ alkyl; in furtherembodiments R₂ is CH₃.

In some embodiments R₆ is a chlorine atom. In some embodiments,compounds can be represented by Formula (Is) as illustrated below:

wherein each variable in Formula (Is) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (Is) and R₂ is C₁₋₄ alkyl in furtherembodiments, R₂ is CH₃.

In some embodiments R₆ is a bromine atom. In some embodiments R₆ is aniodine atom.

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is C₁₋₄ haloalkyl. In some embodiments R₆ is CF₃.

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is nitro.

Some embodiments of the present invention are compounds of Formula (I)wherein R₆ is —OH.

In some embodiments, compounds of the present invention are of Formula(Ic) wherein R₁ is H or C₁₋₈ alkyl, and R₃, R₄, R₅, and R₆ are eachindependently H or halogen.

In some embodiments, compounds of the present invention are of Formula(Ic) wherein R₁ is H or CH₃, and R₃, R₄, R₅, and R₆ are eachindependently H, F, Cl, or Br.

In some embodiments, compounds of the present invention are of Formula(Ic) wherein R₁ is H, and R₃ is H, F, Cl, or Br; R₄ is H or Cl; R₅ is H;and R₆ is H or Cl.

In some embodiments, compounds of the present invention are of Formula(Ic) wherein R₁ is CH₃, and R₃ is H, F, Cl, or Br; R₄ is H or Cl; R₅ isH; and R₆ is H or Cl.

Still further embodiments of the present invention are compounds ofFormula (I) as shown in TABLE 2 below or a pharmaceutically acceptablesalt, hydrate and solvate thereof: TABLE 2 (I)

R₁ R₂ R₃ R₄ R₅ R₆ H CH₃ Cl H H Cl H CH₃ Cl H Cl H H CH₃ Cl Cl H H H CH₃Cl H H H H CH₃ H H Cl Cl H CH₃ H Cl H Cl H CH₃ Cl H H Cl H CH₃ H H H ClH CH₃ F H H Cl H CH₃ F H Cl H H CH₃ F Cl H H H CH₃ F H H H H CH₃ H H ClF H CH₃ H Cl H F H CH₃ Cl H H F H CH₃ H H H F H CH₃ Br Cl H H CH₃ CH₃ ClH H Cl CH₃ CH₃ Cl H Cl H CH₃ CH₃ Cl Cl H H CH₃ CH₃ Cl H H H CH₃ CH₃ H HCl Cl CH₃ CH₃ H CL H Cl CH₃ CH₃ Cl H H Cl CH₃ CH₃ H H H Cl CH₃ CH₃ F H HCl CH₃ CH₃ F H Cl H CH₃ CH₃ F Cl H H CH₃ CH₃ F H H H CH₃ CH₃ H H Cl FCH₃ CH₃ H Cl H F CH₃ CH₃ Cl H H F CH₃ CH₃ H H H F CH₃ CH₃ Cl H H Cl CH₃CH₃ Cl H Cl H CH₃ CH₃ Br Cl H H

Some embodiments of the present invention are compounds of Formula (I)selected from the group consisting of:6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or apharmaceutically acceptable salt, hydrate and solvate thereof.

Some embodiments of the present invention are compounds of Formula (I)selected from the group consisting of:6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or apharmaceutically acceptable salt, hydrate and solvate thereof.

Some embodiments of the present invention are compounds of Formula (I)selected from the group consisting of:N-methyl-6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;N-methyl-8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; andN-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, hydrate and solvate thereof.

Some embodiments of the present invention are compounds of Formula (I)selected from the group consisting of:(R)-6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(R)-6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(R)-8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(R)-8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and(R)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or apharmaceutically acceptable salt, hydrate and solvate thereof.

Some embodiments of the present invention are compounds of Formula (I)selected from the group consisting of:(S)-6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(S)-6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(S)-8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(S)-8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and(S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or apharmaceutically acceptable salt, hydrate and solvate thereof.

Some embodiments of the present invention are compounds of Formula (I)selected from the group consisting of:(R)-N-methyl-6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(R)-N-methyl-6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(R)-N-methyl-8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(R)-N-methyl-8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;and(R)-N-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, hydrate and solvate thereof.

Some embodiments of the present invention are compounds of Formula (I)selected from the group consisting of:(S)-N-methyl-6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(S)-N-methyl-6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(S)-N-methyl-8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;(S)-N-methyl-8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;and(S)-N-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt, hydrate and solvate thereof.

At various places in the present specification substituents of compoundsof the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₄ alkyl” is specifically intended to individuallyand separately disclose methyl, ethyl, C₃ alkyl and C₄ alkyl.

Methods and Use

One aspect of the present invention pertains to methods of modulating a5HT_(2C) receptor comprising contacting said receptor with atherapeutically effective amount or dose of a compound as describedherein. Preferably, compounds of the present invention are agonists ofthe 5HT_(2C) receptor.

Another aspect of the present invention pertains to methods ofprophylaxis or treatment of a 5HT_(2C) receptor associated disease in anindividual comprising administering to the individual in need of suchprophylaxis or treatment a therapeutically effective amount or dose of acompound of the present invention or a pharmaceutical compositionthereof. In some embodiments, the 5HT_(2C) receptor associated diseaseis selected from the group consisting of disorders of the centralnervous system; damage to the central nervous system; cardiovasculardisorders; gastrointestinal disorders; diabetes insipidus and sleepapnea. In some embodiments, the individual is a mammal. Preferably, themammal is a human.

In some embodiments, the 5HT_(2C) receptor associated related disease isselected from the group consisting of depression, atypical depression,bipolar disorders, anxiety, anxiety disorders, obsessive-compulsivedisorders, social phobias, panic states, attention deficit hyperactivitydisorder, disruptive behavior disorders, impulse control disorders,borderline personality disorder, sleep disorders (e.g., sleep apnea),autism, seizure disorders, mutism, selective mutism, childhood anxietydisorders, sexual dysfunction in males (e.g., premature ejaculation anderectile difficulty or dysfunction), sexual dysfunction in females,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, Alzheimer disease, age-related behavioraldisorders, behavioral disorders associated with dementia, dementia ofaging, organic mental disorders, mental disorders in childhood,aggressivity, age-related memory disorders, memory loss, chronic fatiguesyndrome, drug and alcohol addiction, alcoholism, tobacco abuse, weightloss, obesity, bulimia, bulimia nervosa, anorexia nervosa, binge eatingdisorder, premenstrual tension, premenstrual syndrome (PMS or lateluteal phase dysphoric disorder), post-traumatic syndrome, spinal cordinjury, damage of the central nervous system (e.g., trauma, stroke,neurodegenerative diseases or toxic or infective disorders (e.g.,thrombosis), gastrointestinal disorders (e.g., dysfunction ofgastrointestinal motility), diabetes insipidus, and type II diabetes.

In some embodiments, the 5HT_(2C) receptor associated disease isselected from the group consisting of high blood pressure, hypertension,high blood cholesterol, dyslipidemia, type II (non-insulin dependent)diabetes, insulin resistance, glucose intolerance, hyperinsulinemia,coronary heart disease, angina pectoris, congestive heart failure,stroke, gallstones, cholescystitis and cholelithiasis, gout,osteoarthritis, obstructive sleep apnea and respiratory problems, sometypes of cancer (such as endometrial, breast, prostate, and colon),complications of pregnancy, poor female reproductive health (such asmenstrual irregularities, infertility, irregular ovulation), bladdercontrol problems (such as stress incontinence), uric acidnephrolithiasis, psychological disorders (such as depression, eatingdisorders, distorted body image, and low self esteem).

In some embodiments, the 5HT_(2C) receptor associated disease isselected from the group consisting of psychiatric symptoms and behaviorsin individuals with eating disorders such as, but not limited to,anorexia nervosa and bulimia nervosa. Individuals with eating disordersoften demonstrate social isolation. For example, anorexic individualsoften present symptoms of being depressed, anxious, obsession,perfectionistic traits, and rigid cognitive styles as well as sexualdisinterest. In addition to anorexia nervosa and bulimia nervosa, othereating disorders include, binge eating disorder (compulsive eating) andED-NOS (i.e., eating disorders not otherwise specified—an officialdiagnosis). An individual diagnosed with ED-NOS possess atypical eatingdisorders including situations in which the individual meets all but afew of the criteria for a particular diagnosis. In essence, what theindividual is doing with regard to food and weight is neither normal norhealthy.

In some embodiments, the 5HT_(2C) receptor associated disease isselected from the group consisting of anorexia athletica (compulsiveexercising), body dysmorphic disorder (bigorexia), infection-triggeredauto immune subtype of anorexia in children, orthorexia nervosa,night-eating syndrome, nocturnal sleep-related eating disorder,rumination syndrome, gourmand syndrome, Prader-Willi syndrome, pica, andcyclic vomiting syndrome.

Another aspect of the present invention pertains to methods ofdecreasing food intake of an individual comprising administering to theindividual a therapeutically effective amount or dose of a compound ofthe present invention or a pharmaceutical composition thereof. In someembodiments, the individual is a mammal. Preferably, the mammal is ahuman. In further embodiments, the human has a body mass index of about18.5 to about 45. In further embodiments, the human has a body massindex of about 25 to about 45. In further embodiments, the human has abody mass index of about 30 to about 45. In further embodiments, thehuman has a body mass index of about 35 to about 45.

Another aspect of the present invention pertains to methods of inducingsatiety in an individual comprising administering to said individual atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. In some embodiments,the individual is a mammal. Preferably, the mammal is a human. Infurther embodiments, the human has a body mass index of about 18.5 toabout 45. In further embodiments, the human has a body mass index ofabout 25 to about 45. In further embodiments, the human has a body massindex of about 30 to about 45. In further embodiments, the human has abody mass index of about 35 to about 45.

Another aspect of the present invention pertains to methods ofcontrolling weight gain of an individual comprising administering tosaid individual suffering from weight control a therapeuticallyeffective amount or dose of a compound of the present invention or apharmaceutical composition thereof. In some embodiments, the individualis a mammal. Preferably, the mammal is a human. In further embodiments,the human has a body mass index of about 18.5 to about 45. In furtherembodiments, the human has a body mass index of about 25 to about 45. Infurther embodiments, the human has a body mass index of about 30 toabout 45. In further embodiments, the human has a body mass index ofabout 35 to about 45.

Another aspect of the present invention pertains to methods of producinga pharmaceutical composition comprising admixing at least one compoundof the present invention and at least one pharmaceutically acceptablecarrier.

Another aspect of the present invention pertains to compounds, asdescribed herein, for use in a method of prophylaxis or treatment ofdisorders of the central nervous system; damage to the central nervoussystem; cardiovascular disorders; gastrointestinal disorders; diabetesinsipidus or sleep apnea of the human or animal body by therapy.

Another aspect of the present invention pertains to use of compounds, asdescribed herein, for the manufacture of a medicament for use in thetreatment or prophylaxis of disorders of the central nervous system;damage to the central nervous system; cardiovascular disorders;gastrointestinal disorders; diabetes insipidus or sleep apnea.

In some embodiments, the disorders of the central nervous system areselected the group consisting of depression, atypical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, Alzheimer disease, age-related behavioraldisorders, behavioral disorders associated with dementia, organic mentaldisorders, mental disorders in childhood, aggressivity, age-relatedmemory disorders, chronic fatigue syndrome, drug and alcohol addiction,obesity, bulimia, anorexia nervosa and premenstrual tension. In furtherembodiments, the disorder of the central nervous system is obesity. Infurther embodiments, the disorder of the central nervous system isAlzheimer disease. In further embodiments, the sexual dysfunction isMale erectile dysfunction.

In some embodiments, the damage to the central nervous system is bytrauma, stroke, neurodegenerative diseases, toxic CNS diseases orinfective CNS diseases. In further embodiments, the damage to thecentral nervous system is by encephalitis or meningitis.

In some embodiments, the cardiovascular disorder is thrombosis.

In some embodiments, the gastrointestinal disorder is dysfunction ofgastrointestinal motility.

Another aspect of the present invention pertains to methods of producinga pharmaceutical composition comprising admixing at least one compoundof the present invention and at least one pharmaceutically acceptablecarrier.

Another aspect of the present invention pertains to compounds, asdescribed herein, for use in a method of treatment of the human oranimal body by therapy.

Another aspect of the present invention pertains to compounds, asdescribed herein, for use in a method of prophylaxis or treatment ofdisorders of the central nervous system; damage to the central nervoussystem; cardiovascular disorders; gastrointestinal disorders; diabetesinsipidus or sleep apnea of the human or animal body by therapy.

Another aspect of the present invention pertains to use of compounds, asdescribed herein, for the manufacture of a medicament for use in thetreatment or prophylaxis of disorders of the central nervous system;damage to the central nervous system; cardiovascular disorders;gastrointestinal disorders; diabetes insipidus or sleep apnea.

Another aspect of the present invention pertains to the use of acompound of the present invention with agonist activity at the serotonin5HT_(2C) receptor for the treatment and/or prophylaxis of AD and ADrelated disorders. The compounds of the present invention can be usedalone or in combination with another agent or agents (such as but notlimited to AChE inhibitors) that are typically prescribed for AD.

Combination Therapy—Prophylaxis and Treatment

In the context of the present invention, a compound of Formula (I) orpharmaceutical composition thereof can be utilized for modulating theactivity of the 5HT_(2C) receptor associated diseases, conditions and/ordisorders as described herein. Examples of modulating the activity of5HT_(2C) receptor associated diseases include the prophylaxis ortreatment of obesity and/or overweight by decreasing food intake,inducing satiation (i.e., the feeling of fullness), controlling weightgain, decreasing body weight and/or affecting metabolism such that therecipient loses weight and/or maintains weight. Such compounds andpharmaceutical compositions can therefore be used in the context ofdisorders and/or diseases where weight gain is a component of a diseaseand/or disorder such as those listed herein. Furthermore, compounds andcomposition of the present invention can be used for the prophylaxisand/or treatment of Alzheimer Disease, erectile dysfunction and other5HT_(2C) receptor associated diseases and/or disorders described herein.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent (i.e., mono-therapy), they can also be usedin combination with other pharmaceutical agents (i.e.,combination-therapy) for the treatment of thediseases/conditions/disorders described herein. Therefore, anotheraspect of the present invention includes methods of prophylaxis and/ortreatment comprising administering to an individual in need ofprophylaxis and/or treatment a therapeutically effective amount of acompound of the present invention, for example Formula (I), incombination with one or more additional pharmaceutical agent asdescribed herein.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, MCR4 agonists, cholescystokinin-A (CCK-A)agonists, serotonin and norepinephrine reuptake inhibitors (for example,sibutramine), sympathomimetic agensts, β₃ adrenergic receptor agonists,dopamine agonists (for example, bromocriptine), melanocyte-stimulatinghormone receptor analogs, cannabinoid 1 receptor antagonists [forexample, SR141716:N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide],melanin concentrating hormone antagonists, leptons (the OB protein),leptin analogues, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y antagonists,thyromimetic agents, dehydroepiandrosterone or an analogue thereof,glucocorticoid receptor agonists or antagonists, orexin receptorantagonists, urocortin binding protein antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neutrotrophic factors (such asAxokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.and Procter & Gamble Company, Cincinnati, Ohio), human agouti-relatedproteins (AGRP), ghrelin receptor antagonists, histamine 3 receptorantagonists or reverse agonists, neuromedin U receptor agonists,noradrenergic anorectic agents (for example, phentermine, mazindol andthe like) and appetite suppressants (for example, bupropion).

Other anti-obesity agents, including the agents set forth infra, arewell known, or will be readily apparent in light of the instantdisclosure, to one of ordinary skill in the art.

In some embodiments, the anti-obesity agents are selected from the groupconsisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin,and pseudoephedrine. In a further embodiment, compounds of the presentinvention and combination therapies are administered in conjunction withexercise and/or a sensible diet.

It will be understood that the scope of combination-therapy of thecompounds of the present invention with other anti-obesity agents,anorectic agents, appetite suppressant and related agents is not limitedto those listed above, but includes in principle any combination withany pharmaceutical agent or pharmaceutical composition useful for thetreatment of overweight and obese individuals.

Other suitable pharmaceutical agents, in addition to anti-obesityagents, that can be used in combination with the compounds of thepresent invention include agents useful in the treatment of concomitantdiseases. For example, individuals that are over weight or obeseincrease their risk of morbidity and mortality arising from concomitantdiseases, such as, but not limited to, congestive heart failure, type IIdiabetes, atherosclerosis, dyslipidemia, hyperinsulinemia, hypertension,insulin resistance, hyperglycemia, retinopathy, nephropathy andneuropathy. Treatment for one or more of the diseases cited hereininclude the use of one or more pharmaceutical agents known in the artbelonging to the classes of drugs referred to, but not limited to, thefollowing: sulfonylureas, meglitinides, biguanides, α-glucosidaseinhibitors, peroxisome proliferators-activated receptor-γ (i.e., PPAR-γ)agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,cholesterol-lowering drugs (for example, fibrates that include:fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bileacid sequestrants which include: cholestyramine, colestipol and thelike; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists and adiponectin. In accordance toone aspect of the present invention, a compound of the present can beused in combination with a pharmaceutical agent or agents belonging toone or more of the classes of drugs cited herein.

It will be understood that the scope of combination-therapy of thecompounds of the present invention with other pharmaceutical agents isnot limited to those listed herein, supra or infra, but includes inprinciple any combination with any pharmaceutical agent orpharmaceutical composition useful for the treatment diseases, conditionsor disorders that are linked to overweight and obese individuals.

Some embodiments of the present invention include methods of prophylaxisor treatment of a disease, disorder or condition as described hereincomprising administering to an individual in need of such prophylaxis ortreatment a therapeutically effect amount or dose of a compound of thepresent invention in combination with at least one pharmaceutical agentselected from the group consisting of: sulfonylureas, meglitinides,biguanides, α-glucosidase inhibitors, peroxisome proliferators-activatedreceptor-γ (i.e., PPAR-γ) agonists, insulin, insulin analogues, HMG-CoAreductase inhibitors, cholesterol-lowering drugs (for example, fibratesthat include: fenofibrate, bezafibrate, gemfibrozil, clofibrate and thelike; bile acid sequestrants which include: cholestyramine, colestipoland the like; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists and adiponectin. In someembodiments, methods of the present invention include compounds of thepresent invention and the pharmaceutical agents are administeredseparately. In further embodiments, compounds of the present inventionand the pharmaceutical agents are administered together.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include α-glucosidase inhibitors.α-Glucosidase inhibitors belong to the class of drugs whichcompetitively inhibit digestive enzymes such as α-amylase, maltase,α-dextrinase, sucrase, etc. in the pancreas and or small intestine. Thereversible inhibition by α-glucosidase inhibitors retard, diminish orotherwise reduce blood glucose levels by delaying the digestion ofstarch and sugars. Some representative examples of α-glucosidaseinhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine(generic name; voglibose), miglitol, and α-glucosidase inhibitors knownin the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include sulfonylureas. Thesulfonylureas (SU) are drugs which promote secretion of insulin frompancreatic β cells by transmitting signals of insulin secretion via SUreceptors in the cell membranes. Examples of the sulfonylureas includeglyburide, glipizide, glimepiride and other sulfonylureas known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the meglitinides. Themeglitinides are benzoic acid derivatives represent a novel class ofinsulin secretagogues. These agents target postprandial hyperglycemiaand show comparable efficacy to sulfonylureas in reducing HbA_(1c).Examples of meglitinides include repaglinide, nateglinide and othermeglitinides known in the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the biguanides. Thebiguanides represent a class of drugs that stimulate anaerobicglycolysis, increase the sensitivity to insulin in the peripheraltissues, inhibit glucose absorption from the intestine, suppress ofhepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples ofbiguanides include phenformin, metformin, buformin, and biguanides knownin the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the α-glucosidase inhibitors.The α-glucosidase inhibitors competitively inhibit digestive enzymessuch as α-amylase, maltase, α-dextrinase, sucrase, etc. in the pancreasand or small intestine. The reversible inhibition by α-glucosidaseinhibitors retard, diminish or otherwise reduce blood glucose levels bydelaying the digestion of starch and sugars. Examples of α-glucosidaseinhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine(generic name; voglibose), miglitol, and α-glucosidase inhibitors knownin the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the peroxisomeproliferators-activated receptor-γ (i.e., PPAR-γ) agonists. Theperoxisome proliferators-activated receptor-γ agonists represent a classof compounds that activates the nuclear receptor PPAR-γ and thereforeregulate the transcription of insulin-responsive genes involved in thecontrol of glucose production, transport and utilization. Agents in theclass also facilitate the regulation of fatty acid metabolism. Examplesof PPAR-γ agonists include rosiglitazone, pioglitazone, tesaglitazar,netoglitazone, GW-409544, GW-501516 and PPAR-γ agonists known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the HMG-CoA reductaseinhibitors. The HMG-CoA reductase inhibitors are agents also referred toas Statin compounds that belong to a class of drugs that lower bloodcholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA)reductase. HMG-CoA reductase is the rate-limiting enzyme in cholesterolbiosynthesis. The statins lower serum LDL concentrations by upregulatingthe activity of LDL receptors and are responsible for clearing LDL fromthe blood. Some representative examples the statin compounds includerosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin,atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin,BMS's “superstatin”, and HMG-CoA reductase inhibitors known in the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the angiotensin convertingenzyme (ACE) inhibitors. The angiotensin converting enzyme inhibitorsbelong to the class of drugs that partially lower blood glucose levelsas well as lowering blood pressure by inhibiting angiotensin convertingenzymes. Examples of the angiotensin converting enzyme inhibitorsinclude captopril, enalapril, alacepril, delapril; ramipril, lisinopril,imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril,trandolapril, and angiotensin converting enzyme inhibitors known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the angiotensin II receptorantagonists. Angiotensin II receptor antagonists target the angiotensinII receptor subtype 1 (i.e., AT1) and demonstrate a beneficial effect onhypertension. Examples of angiotensin II receptor antagonists includelosartan (and the potassium salt form), and angiotensin II receptorantagonists known in the art.

Other treatments for one or more of the diseases cited herein includethe use of pharmaceutical agents known in the art belonging to theclasses of drugs referred to, but not limited to, the following: amylinagonists (for example, pramlintide), insulin secretagogues (for example,GLP-1 agonists; exendin-4; insulinotropin (NN2211); dipeptyl peptidaseinhibitors (for example, NVP-DPP-728), acyl CoA cholesterolacetyltransferase inhibitors (for example, Ezetimibe, eflucimibe, andlike compounds), cholesterol absorption inhibitors (for example,ezetimibe, pamaqueside and like compounds), cholesterol ester transferprotein inhibitors (for example, CP-529414, JTT-705, CETi-1, and likecompounds), microsomal triglyceride transfer protein inhibitors (forexample, implitapide, and like compounds), cholesterol modulators (forexample, NO-1886, and like compounds), bile acid modulators (forexample, GT103-279 and like compounds) and squalene synthase inhibitors.

Squalene synthesis inhibitors belong to a class of drugs that lowerblood cholesterol levels by inhibiting synthesis of squalene. Examplesof the squalene synthesis inhibitors include(S)-α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, mono potassium salt (BMS-188494) and squalene synthesis inhibitorsknown in the art.

Compositions of the Present Invention

According to a further aspect, the present invention also pertains topharmaceutical compositions comprising one or more compounds of Formula(I) or any formulae disclosed herein, and one or more pharmaceuticallyacceptable carriers.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions, and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro, A. R., et al.).

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may, in an alternative use, be administered asa raw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5HT_(2C) receptor agonists.By the term “active ingredient” is defined in the context of a“pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits, and as is customary and is known to the physician,it is to be tailored to the individual conditions in each individualcase. It depends, for example, on the nature and severity of the illnessto be treated, on the condition of the patient, on the compound employedor on whether an acute or chronic disease state is treated orprophylaxis is conducted or on whether further active compounds areadministered in addition to the compounds of the present invention.Representative doses of the present invention include, but not limitedto, about 0.001 mg to about 5000 mg, about 0.001 to about 2500 mg, about0.001 to about 1000 mg, 0.001 to about 500 mg, 0.001 mg to about 250 mg,about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001mg to about 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4, doses. Depending on the individual and as deemedappropriate from the patient's physician or care-giver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, active salt or hydrate thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill ultimately be at the discretion of the attendant physician orclinician.

In general, one skilled in the art understands how to extrapolate invivo data obtained in a model system, typically an animal model, toanother, such as a human. Typically, animal models include, but are notlimited to, rodent models. In some circumstances, these extrapolationsmay merely be based on the weight of the animal model in comparison toanother, such as a mammal, preferably a human, however, more often,these extrapolations are not simply based on weights, but ratherincorporate a variety of factors. Representative factors include, butare not limited to, the type, age, weight, sex, diet and medicalcondition of the patient, the severity of the disease, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized, onwhether an acute or chronic disease state is being treated orprophylaxis is conducted or on whether further active compounds areadministered in addition to the compounds of the Formula (I) as part ofcombination-therapy. The dosage regimen for treating a disease conditionwith the compounds and/or compositions of the present invention isselected in accordance with a variety factors as cited above. Thus, theactual dosage regimen employed may vary widely and therefore may deviatefrom a preferred dosage regimen and one skilled in the art willrecognize that dosage and dosage regimen outside these typical rangescan be tested and, where appropriate, may be used in the methods of thisinvention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavouringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of theFormula (I) or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the Formula (I) as an aerosol can be prepared by processeswell-known to the person skilled in the art. For their preparation, forexample, solutions or dispersions of the compounds of the Formula (I) inwater, water/alcohol mixtures or suitable saline solutions can beemployed using customary additives, for example benzyl alcohol or othersuitable preservatives, absorption enhancers for increasing thebioavailability, solubilizers, dispersants and others, and, ifappropriate, customary propellants, for example include carbon dioxide,CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2 (1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Ingeneral, the “pro-drug” approach is utilized to facilitate oralabsorption. A thorough discussion is provided in T. Higuchi and V.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, at least one pharmaceutical agent asdescribed herein and a pharmaceutically acceptable carrier.

In some embodiments the pharmaceutical agents is selected from the groupconsisting of: apolipoprotein-B secretion/microsomal triglyceridetransfer protein (apo-B/MTP) inhibitors, MCR-4 agonists,cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrinereuptake inhibitors (for example, sibutramine), sympathomimetic agensts,β₃ adrenergic receptor agonists, dopamine agonists (for example,bromocriptine), melanocyte-stimulating hormone receptor analogs,cannabinoid 1 receptor antagonists [for example, SR141716:N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide],melanin concentrating hormone antagonists, leptons (the OB protein),leptin analogues, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y antagonists,thyromimetic agents, dehydroepiandrosterone or an analogue thereof,glucocorticoid receptor agonists or antagonists, orexin receptorantagonists, urocortin binding protein antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neutrotrophic factors (such asAxokine™), human agouti-related proteins (AGRP), ghrelin receptorantagonists, histamine 3 receptor antagonists or reverse agonists,neuromedin U receptor agonists, noradrenergic anorectic agents (forexample, phentermine, mazindol and the like) and appetite suppressants(for example, bupropion). In further embodiments, the pharmaceuticalagent is selected from the group consisting of orlistat, sibutramine,bromocriptine, ephedrine, leptin, and pseudoephedrine.

In some embodiments the pharmaceutical agents is selected from the groupconsisting of: sulfonylureas, meglitinides, biguanides, α-glucosidaseinhibitors, peroxisome proliferators-activated receptor-γ (i.e., PPAR-γ)agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,cholesterol-lowering drugs (for example, fibrates that include:fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bileacid sequestrants which include: cholestyramine, colestipol and thelike; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists and adiponectin.

It is noted that when the 5HT_(2C) receptor agonists are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of 5HT_(2C) receptor agonists for thetreatment of obesity in domestic animals (e.g., cats and dogs), and5HT_(2C) receptor agonists in other domestic animals where no disease ordisorder is evident (e.g., food-oriented animals such as cows, chickens,fish, etc.). Those of ordinary skill in the art are readily creditedwith understanding the utility of such compounds in such settings.

Preparation of Compounds of the Invention

In the illustrated syntheses outlined below, the labeled substituentshave the same identifications as set out in the definitions of thecompounds of the present invention of Formula (I) and the Formulae ofthe subgenera as described herein.

Those of skill in the art will appreciate the wide variety of compoundsof the present invention can be prepared according to Schemes I throughV, Infra. One representative synthesis is set forth below in Scheme I,for when R₂ is methyl:

By utilizing, for example, an appropriately substituted 2-phenylethylamino Compound A having any of a wide variety of substituents R₃,R₄, R₅ and R₆ the corresponding substituted1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound H can beprepared. In a subsequent step, Compound H can be readily alkylated by,for example, treatment with excess formaldehyde or formaldehydeequivalent such as paraformaldehyde (for methylation) or a higher orderaldehyde, followed by reduction with NaBH₃CN or similar reducing agentaccording to methodologies known in the art.

In addition, numerous synthetic transformations can be performed atdifferent stages in the pathway illustrated in Scheme I to prepareadditional compounds of Formula (I). For example, Compound E can beconverted into a number of compounds of the invention including,R₂=—CH₂OH. In this case, the double bond of Compound E can behydroborated using methods known in the art, such as diborane,disiamylborane and the like, to give a primary alcohol after oxidativeworkup (i.e., H₂O₂). Either the N-protection can be removed to givedesired compounds of the invention or the primary alcohol can besubsequently converted to an ether using methods known in the art suchas, for example, the Williamson ether procedure, using an alkyl halidein the presence of a base. In this example, the N-protection can beremoved to give compounds of Formula (I) wherein R₂ is the groupCH₂O—C₁₋₄ alkyl. Alternatively, the primary alcohol can be fluorinatedusing reagents known in the art, such as dialkylaminosulfur trifluoridesand the like. Certain dialkylaminosulfur trifluorides include, but notlimited to, bis(2-methoxyethyl)amino-sulfur trifluoride,(diethylamino)sulfur trifluoride, (dimethylamino)sulfur trifluoride,morpholinosulfur trifluoride and the like. Treatment with a fluorinatingagent can give monofluoroalkyl compounds of Formula (I), wherein R₂ is—CH₂F. In addition, the primary alcohol prepared from Compound E can befurther oxidized to give the corresponding aldehyde and in a similarmanner subsequently converted to difluoroalkyl compounds of Formula (I),wherein R₂ is —CHF₂.

Reaction Scheme II is provided below showing these illustrativetransformations and is not intended to be limiting:

Another representative synthetic pathway for the preparation ofcompounds of Formula (I) is set forth below in Reaction Scheme III:

By utilizing, for example, an appropriately substituted 2-phenylethylamino Compound A having any of a wide variety of substituents R₃,R₄, R₅ and R₆ the corresponding1-substituted-2,3,4,5-tetrahydro-1H-3-benzazepine [i.e., a compound ofFormula (Ia)] can be prepared. Scheme III illustrates one generalpathway for the introduction of R₂ groups into the compounds of thepresent invention. Compound A is acylated with a carboxylic acidderivative using one of the many methods, such as one of the commonlyknown coupling agents, available to the artisan. A particularly usefulmethod uses an acid chloride as described in the Examples, Infra. Thecarboxylic acid derivative is selected to possess a leaving group or amoiety that can be converted into a leaving group (i.e., Lg). Theresulting Compound K is cyclized in the presence of a Lewis Acid, suchas, for example, aluminum chloride. After reduction, compounds of theinvention are obtained wherein R₁ is H [i.e., a compound of Formula(Ia)].

One alternate synthetic approach that can be used to prepare compoundsof the present invention utilizes Compound L (i.e., R₂ is H). In thismethod, the amide nitrogen is first alkylated (providing the R₁ group,Compound N) or protected (i.e., Compound O) using any number of themethods known in the art. The R₂ group is subsequently introduced via analkylation reaction to provide Compounds P and Q respectively.Alkylation reactions can be conducted under basic conditions, forexample, using DMF/NaH, and an alkylating agent of the formula R₂-Lg(wherein: R₂ has the same meaning as described herein and Lg is aleaving group known in the art, such as, Cl, Br, I, OMs, OTs and thelike). Examples of the alkylating agent include, but are not limited to,CH₃I, CH₃OMs, CH₃OTs, CH₃CH₂I, CF₃CH₂I, CF₃I, CH₃OCH₂Cl and the like. Arepresentative alkylation example has been reported by Orito, K. andMatsuzaki, T. in Tetrahedron, 1980, 36, 81, 1017-1021 and isincorporated herein by reference in its entirety. In the example whenthe nitrogen is protected (i.e., Compound Q), the protecting group isfirst removed and the amide reduced to provide compounds of theinvention wherein R₁ is H. In the example where the nitrogen isalkylated (i.e., Compound P), then the amide is merely reduced toprovide compounds wherein R₁ is alkyl. This method is illustrated inSchemes IV and V below:

Those of skill in the art will appreciate that a wide variety ofcompounds of the present invention can be prepared according to SchemesI through V.

Protecting groups may be required for various functionality orfunctionalities during the synthesis of some of the compounds of theinvention. Accordingly, representative protecting groups that aresuitable for a wide variety of synthetic transformations are disclosedin Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, New York, 1999, the disclosure of which isincorporated herein by reference in its entirety.

As described herein, compounds of the present invention can exist invarious forms, for example, enantiomers and racemates. In is understoodthat the optically active forms can be obtained by resolution of theracemates, separated by chiral chromatography or by asymmetric synthesisusing methods known in the art to obtain enantiomers.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of Formula (I) that would be useful not only in radio-imagingbut also in assays, both in vitro and in vivo, for localizing andquantitating the 5HT_(2C) receptor in tissue samples, including human,and for identifying 5HT_(2C) receptor ligands by inhibition binding of aradio-labeled compound. It is a further object of this invention todevelop novel 5HT_(2C) receptor assays of which comprise suchradio-labeled compounds.

The present invention embraces isotopically-labeled compounds of Formula(I) and any subgenera herein, such as but not limited to, Formula (Ia)through Formula (Is). An “isotopically” or “radio-labeled” compounds arethose which are identical to compounds disclosed herein, but for thefact that one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ²H (also written as Dfor deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I,¹²⁵I and ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro 5HT_(2C) receptorlabeling and competition assays, compounds that incorporate ³H, ¹⁴C,⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula (I) that has incorporated at least one radionuclide;in some embodiments the radionuclide is selected from the groupconsisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes supra and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the more scarce radio-isotope ornonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas—This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]—This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]—This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions—This procedure transforms an aryl orheteroaryl amine into a diazonium salt, such as a tetrafluoroboratesalt, and subsequently to ¹²⁵I labeled compound using Na¹²⁵I. Arepresented procedure was reported by Zhu, D.-G. and co-workers in J.Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols—This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labeled Compd Radiopharm. 1999, 42,S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I—This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresented procedure was reported by Bas, M.-D. and co-workers in J.Labeled Compd Radiopharm. 2001, 44, S280-S282.

A radio-labeled 5HT_(2C) receptor compound of Formula (I) can be used ina screening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula (I)” to the 5HT_(2C) receptor. Accordingly, theability of a test compound to compete with the “radio-labeled compoundof Formula (I)” for the binding to the 5HT_(2C) receptor directlycorrelates to its binding affinity.

The labeled compounds of the present invention bind to the 5HT_(2C)receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM, and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1

Intracellular IP₃ Accumulation Assay:

HEK293 cells were transfected in 15 cm sterile dishes with or without(control) 16 ug of human 5HT_(2C) receptor cDNA [for example see,Saltzman, A. G., et al. Biochem. Biophys. Res. Commun. 181, 1469-1478(1991)] using 25 ul of lipofectamine. Cells were then incubated for 3-4hours at 37° C./5% CO₂ and then transfection media was removed andreplaced with 100 ul of DMEM. Cells were then plated onto 100 cm steriledishes. The next day cells were plated into 96 well PDL microtiterplates at a density of 55K/0.2 ml. Six hours latter, media was exchangedwith [³H]inositol (0.25 uCi/well) in inositol free DMEM and plates wereincubated at 37° C./5% CO₂ overnight. The next day, wells were aspiratedand 200 ul of DMEM containing test compound, 10 uM pargyline, and 10 mMLiCl was added to appropriate wells. Plates were then incubated at 37°C./5% CO₂ for three hours followed aspiration and by addition of freshice cold stop solution (1M KOH, 19 mM Na-borate, 3.8 mM EDTA) to eachwell. Plates were kept on ice for 5-10 min and the wells wereneutralized by addition of 200 ul of fresh ice cold neutralizationsolution (7.5% HCl). Plates were then frozen until further processing isdesired. The lysate was then transferred into 1.5 ml Eppendorf tubes and1 ml of chloroform/methanol (1:2) was added/tube. The solution wasvortexed for 15 seconds and the upper phase was applied to a BioradAG1-X8™ anion exchange resin (100-200 mesh). First, the resin was washedwith water at 1:1.25 W/V and 0.9 ml of upper phase was loaded onto thecolumn. The column was then washed with 10 ml of 5 mM myo-inositol and10 ml of 5 mM Na-borate/60 mM Na-formate. The inositol tris phosphateswere eluted into scintillation vials containing 10 ml of scintillationcocktail with 2 ml of 0.1 M formic acid/1 M ammonium formate. Thecolumns were regenerated by washing with 10 ml of 0.1 M formic acid/3Mammonium formate and rinsed twice with dd H₂O and stored at 4° C. inwater.

The biological activities in the IP Accumulation Assay for severalrepresentative compounds are shown in Table 3 below: TABLE 3 5HT_(2C)(IC₅₀) Compound No. IP Accumulation Assay (nM) 1 11.7 3 24.5

The majority of the compounds of the Examples showed activities in theIP Accumulation Assay in the range between about 11 nM and about 5 μM.

Example 2

Inhibition of Food Intake in Food-Deprived Rats

Male Sprague-Dawley rats (250-350 g) are deprived of food overnightprior to testing. Prior to food deprivation, the animals are weighed andseparated into treatment groups in order to balance groups according tobody weight. On the test day, animals are placed into individual cages(no bedding) at 9:00 am with free access to water. At 10:00 am, animalsare injected with test compound (p.o., i.p., or s.c.) and then presentedwith a pre-weighed amount of food in a dish either 60 min (p.o.) or 30min (i.p. and s.c.) after drug administration. Food consumption overdifferent time points is determined by weighing the food cup at 1, 2, 4,and 6 hr after the food is presented. Thus, food consumption is measuredat 2, 3, 5, and 7 hr post-injection in p.o. studies, and at 1.5; 2.5,4.5, and 6.5 hr post-injection in i.p. and s.c. studies.

Example 3

Syntheses of Selected Compounds of the Invention

Example 3.1 Preparation of (R,S)6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Also referredto herein as Compound 1)

Step 1: Preparation of2-chloro-N-[2-(2,4-dichlorophenyl)ethyl]propionamide.

A solution of 2,4-dichlorophenethylamine (1.0 g, 5.3 mmol) indichloromethane (20 mL) was treated with diisopropylethylamine (0.82 g,6.3 mmol) and 2-chloropropionylchloride (0.67 mL, 5.3 mmol)sequentially, and stirred at 20° C. for 4 hours. The mixture was dilutedwith dichloromethane (50 mL), washed with 10% aqueous HCl, brine (20mL), dried with Na₂SO₄ and concentrated, resulting in 1.5 g of thedesired product as a brown oil. MS calculated for C₁₁H₁₂Cl₃NO+H: 280,observed: 280.

Step 2: Preparation of6,8-dichloro-1-methyl-2-oxo-2,3,5-trihydro-1H-3-benzazepine.

Neat 2-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]propionamide (2.5 g, 9.1mmol) and AlCl₃ (3.6 g, 27 mmol) were heated at 150° C. for 18 hourswhile stirring. The product mixture was quenched with water (10 mL),diluted with dichloromethane (100 mL), the organic phase separated,washed with brine (50 mL), dried with Na₂SO₄ and concentrated, resultingin 1.9 g of a brown oil. MS calculated for C₁₁H₁₁Cl₂NO+H: 244, observed:244.

Step 3: Preparation of6,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of6,8-Dichloro-1-methyl-2-oxo-2,3,5-trihydro-1H-3-benzazepine (1.9 g, 7.8mmol) in tetrahydrofuran (50 mL) was treated with 1.0 M borane in THF(20.0 mL, 20.0 mmol), and stirred at 20° C. for 5 hours. The mixture wasquenched with methanol (10 mL), acidified with concentrated HCl (0.2mL), azeotroped with methanol (3×100 mL) and concentrated. Flashchromatography (5% methanol in dichloromethane) resulted in 1.0 g of aclear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.20 (s, 1 H), 6.90 (s, 1 H), 4.30(bs, 1 H), 3.92 (m, 1 H), 3.51 (m, 1 H), 3.37 (m, 2 H), 3.03 (m, 1 H),2.77 (m, 2 H), 1.31 (d, J=8 Hz, 3 H). MS calculated for C₁₁H₁₃Cl₂N+H:230, observed: 230.

Example 3.2 Preparation of (R,S)6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 2)

Compound 2 was prepared utilizing a similar procedure as described forthe preparation of Compound 1. (R,S)6-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtained from2-chlorophenethylamine as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.17 (d, J=8 Hz, 1 H), 6.93 (m, 2 H), 3.97 (bs, 1 H), 3.79 (m, 1 H),3.3-3.1 (m, 3 H), 2.95 (d, J=11 Hz, 1 H), 2.8-2.6 (m, 2 H), 1.3 (d, J=8Hz, 3 H). MS calculated for C₁₁H₁₄ClN+H: 196, observed: 196.

Example 3.3 Preparation of (R,S)8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound3)

Step 1: Preparation ofN-Trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution ofN-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated withSelectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90mmol) and stirred 60 hours at 75° C. The product mixture was poured intowater (200 mL), extracted with EtOAc (200 mL), the organic phase washedwith saturated aqueous NaHCO₃ (2×100 mL), brine (100 mL), dried withNa₂SO₄ and concentrated. The crude product was purified by flashchromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of awhite solid. MS calculated for C₁₃H₁₂ClF₄NO+H: 310, observed: 310.

Step 2: Preparation of8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution ofN-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 25° C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 93 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.06 (dd, J=8, 8 Hz, 1 H), 6.75 (d, J=8 Hz, 1 H), 3.58 (m, 1 H),3.25-3.15 (m, 3 H), 2.93 (d, J=13 Hz, 1 H) 2.75-2.60 (m, 3H), 1.96 (bs,1 H), 1.33 (d, J=8 Hz, 3 H). MS calculated for C₁₁H₁₃ClFN+H: 214,observed: 214.

Example 3.4 Preparation of (R,S)8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 4)

Compound 4 was prepared utilizing a similar procedure as describedherein for the preparation of Compound 1. (R,S)8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was obtainedfrom 3,4-dichlorophenethylamine as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.40 (d, J=8 Hz, 1 H), 7.16 (d, J=8 Hz, 1 H), 4.17 (m, 1 H),3.55 (m, 2 H), 3.5-3.3 (m, 2 H), 3.2-3.0 (m, 2 H), 1.43 (d, J=7 Hz, 3H). MS calculated for C₁₁H₁₃Cl₂N+H: 230, observed: 230.

Example 3.5 Preparation of(S)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound5)

Step 1: Preparation of(S)-N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

(S)-N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas prepared from(S)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing asimilar procedure as described herein for the preparation of Compound 7(one exception is that the resolution step was performed usingD-tartaric acid). ¹H NMR (400 MHz, CDCl₃, mixture of rotamers) δ 7.27(m, 1H), 6.96 (m, 1H), 4.26 (bm, 0.6H), 4.19-4.03 (m, 1.7H), 3.92-3.87(m, 0.8H) 3.75-3.69 (m, 0.8H), 3.47-3.22 (m, 2H), 2.91 (m, 1H),1.28-1.25 (m, 3H). MS calculated for C₁₃H₁₃ClF₃NO+H: 292, observed: 292.

Step 2: Preparation of(S)-N-Trifluoroacetyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of(S)-N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.62 g, 2.1 mmol) in dichloromethane (10 mL) was treated withN-chlorosuccinimide (0.284 g, 2.1 mmol) and trifluoromethanesulfonicacid (0.639 g, 4.2 mmol). The reaction was stirred for 16 h at 20° C.,diluted with water (20 mL) and extracted with dichloromethane (25 mL).The organics were dried with MgSO₄, filtered and concentrated. HPLCpurification was done to provide 0.078 g of a white solid. ¹H NMR (400MHz, CDCl₃, mixture of rotamers) δ 7.32-7.25 (m, 1H), 6.97-6.93 (m, 1H),4.27-4.24 (m, 0.6H), 4.19-4.13 (m, 1H), 4.08-4.01 (m, 1H), 3.91-3.86(0.8H, m), 3.74-3.69 (m, 0.8H:), 3.45-3.37 (m, 1H), 3.31-3.21 (m, 1H),2.96-2.80 (m, 1H), 1.28-1.22 (m, 3H). MS calculated for C₁₃H₁₂Cl₂F₃NO+H:326, observed: 326.

Step 3: Preparation of(S)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of(S)-N-trifluoroacetyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.270 g, 1.2 mmol) in methanol (10 mL) was treated with 15% aqueousNaOH (10 mL), and stirred for 3.5 hours at 25° C. The product mixturewas concentrated, extracted 3 times with CH₂Cl₂ (25 mL), dried withNa₂SO₄ and concentrated to give 0.270 g of a clear oil. ¹H NMR (400 MHz,CDCl₃) δ 7.40 (d, J=8 Hz, 1 H), 7.16 (d, J=8 Hz, 1 H), 4.17 (m, 1 H),3.55 (m, 2 H), 3.5-3.3 (m, 2 H), 3.2-3.0 (m, 2 H), 1.43 (d, J=7 Hz, 3H). MS calculated for C₁₁H₁₃Cl₂N+H: 230, observed: 230.

Example 3.6 Preparation of(S)-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 6)

Step 1: Preparation of(S)-N-Trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of(S)-N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated withSelectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90mmol) and stirred 60 hours at 75° C. The product mixture was poured intowater (200 mL), extracted with EtOAc (200 mL), the organic phase washedwith saturated aqueous NaHCO₃ (2×100 mL), brine (100 mL), dried withNa₂SO₄ and concentrated. The crude product was purified by flashchromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of awhite solid. MS calculated for C₁₃H₁₂ClF₄NO+H: 310, observed: 310.

Step 2: Preparation of(S)-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of(S)-N-trifluoroacetyl-8-chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH(2 mL), and stirred for 3.5 hours at 25° C. The product mixture wasconcentrated, extracted 3 times with CH₂Cl₂ (5 mL), dried with Na₂SO₄and concentrated to give 93 mg of a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.06 (dd, J=8, 8 Hz, 1 H), 6.75 (d, J=8 Hz, 1 H), 3.58 (m, 1 H),3.25-3.15 (m, 3 H), 2.93 (d, J=13 Hz, 1 H) 2.75-2.60 (m, 3H), 1.96 (bs,1 H), 1.33 (d, J=8 Hz, 3 H). MS calculated for C₁₁H₁₃ClFN+H: 214,observed: 214.

Example 3.7 Preparation of(R)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound7)

Step 1: Preparation of 2-(4-chlorophenyl)ethyl-N-2-chloropropionamide

To a 1-liter, 3-necked round bottom flask under argon balloon equippedwith reflux condenser and addition funnel, were added sequentially2-(4-chlorophenyl) ethylamine (30 g, 193 mmol), 400 mL acetonitrile,triethylamine (19.5 g, 193 mmol) and 80 mL acetonitrile. The clearcolorless solution was stirred and cooled to 0° C. 2-Chloropropionylchloride (24.5 g, 193 mmol, distilled) in 5 mL acetonitrile was slowlyadded over 20 minutes to evolution of white gas, formation of whiteprecipitate, and color change of reaction mixture to slight yellow. Anadditional 10 mL of acetonitrile was used to rinse the addition fennel.The mixture was stirred at 0° C. for 30 minutes and then warmed to roomtemperature and stirred vigorously for an additional one hour. Theyellow reaction mixture was concentrated on the rotary evaporator to asolid containing triethylamine hydrochloride (76.36 grams). Thismaterial was taken up in 100 mL ethylacetate and 200 mL water, andstirred vigorously. The layers were separated and the aqueous layer wasextracted with an additional 100 mL ethylacetate. The combined organiclayers were washed twice with 25 mL of saturated brine, dried overmagnesium sulfate, filtered, and concentrated to a light tan solid (41.6grams, 88%). TLC in ethylacetate-hexane, 8:2 showed a major spottwo-thirds of the way up the plate and a small spot at the baseline.Baseline spot was removed as follows: This material was taken up in 40mL of ethylacetate and hexane was added until the solution becamecloudy. Cooling to 0° C. produced a white crystalline solid (40.2 grams,85% yield). The product is a known compound (Hasan et al., Indian J.Chem., 1971, 9(9), 1022) with CAS Registry No. 34164-14-2. LC/MS gaveproduct 2.45 minute; 246.1 M⁺+H⁺. ¹H NMR (CDCl₃): δ 7.2 (dd, 4H, Ar),6.7 (br S, 1H, NH), 4.38 (q, 1H, CHCH₃), 3.5 (q, 2H, ArCH₂CH₂ NH), 2.8(t, 2H, ArCH₂), 1.7 (d, 3H, CH₃). ¹³C NMR (CDCl₃): 169 (1C, C═O), 136(1C, Ar—Cl), 132 (1C, Ar), 130 (2C, Ar), 128 (2C, Ar), 56 (1C, CHCl), 40(1C, CHN), 34 (1C, CHAr), 22 (1C, CH₃).

Step2: Preparation of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one.

2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) andaluminum chloride (16 g, 119.9 mmol) were added to a clean dry 100 mLround bottom flask equipped with an argon balloon, stirring apparatus,and heating apparatus. The white solid melted to a tan oil with bubblingat 91° C. (Note: if impure starting materials are used, a black tar canresult but clean product can still be isolated). The mixture was heatedand stirred at 150° C. for 12 hours. The reaction can be followed byLC/MS with the starting material at 2.45 minutes (246.1 M⁺+H⁺), theproduct at 2.24 minutes (209.6 M⁺+H⁺) on a 5 minute reaction time from5-95% w/0.01% TFA in water/MeCN (50:50). After cooling to roomtemperature, the reaction mixture was quenched with slow addition of 10mL of MeOH followed by 5 mL of 5% HCl in water and 5 mL of ethylacetate. After separation of the resulting layers, the aqueous layer wasextracted a second time with 10 mL of ethyl acetate. The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated to a tan solid (6.78 grams, 80% yield). LC/MS showed onepeak, at 2.2 min and 209.6 MI. This material was taken up in ethylacetate, filtered through celite and Kieselgel 60 (0.5 inch plug on a 60mL Buchner funnel) and the filtrate was recrystallized from hexane/ethylacetate to give final product (4.61 grams, 54% yield). ¹H NMR (CDCl₃): δ7.3-7.1 (m, 3H, Ar), 5.6 (br s, 1H, NH), 4.23 (q, 1H, CHCH₃), 3.8 (m,1H, ArCH₂CH₂ NH), 3.49 (m, 1H, ArCH₂CH₂ NH), 3.48 (m, 1H, ArCH₂ CH₂NH),3.05 (m, 1H, ArCH₂ CH₂NH), 1.6 (d, 3H, CH₂). ¹³C NMR (CDCl₃): 178 (1C,C═O), 139 (1C, Ar), 135 (1C, Ar), 130, 129 (2C, Ar), 126 (2C, Ar), 42(1C, C), 40 (1C, CHN), 33 (1C, CHAr), 14 (1C, CH₃).

Step 3: Preparation of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (150 mg,0.716 mmol, purified by HPLC or recrystallization) was added to a 50 mLround bottom flask with 2M borane-tetrahydrofuran solution (2 mL, 2.15mmol). The mixture was stirred 10 hours at room temperature under anargon balloon. LC/MS showed the desired product as the major peak withapproximately 5% of starting material still present. The reactionmixture was quenched with 5 mL methanol and the solvents were removed onthe rotary evaporator. This procedure was repeated with methanoladdition and evaporation. The mixture was evaporated on the rotaryevaporator followed by 2 hours in vacuo to give the product as a whitesolid (117 mg, 70 % yield). ¹H NMR (CDCl₃): δ 10.2 (br s, 1H), 9.8 (brs, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).LC/MS: 1.41 minute, 196.1 M+H⁺ and 139 major fragment.

Step 4: Preparation of L-(+)-tartaric acid salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

To a clean, dry 50 mL round bottom flask were added 11.5 g (0.06 mol) of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine to 2.23 g (0.015mol) of L-(+)-tartaric acid. The suspension was diluted with 56 g oftert-butanol and 6.5 mL of H₂O. The mixture was heated to reflux (75-78°C.) and stirred for 10 min to obtain a colorless solution. The solutionwas slowly cooled down to room temperature (during 1 h) and stirred for3 h at room temperature. The suspension was filtered and the residue waswashed twice with acetone (10 mL). The product was dried under reducedpressure (50 mbar) at 60° C. to yield 6.3 g of the tartrate salt(ee=80). This tartrate salt was added to 56 g of tert-butanol and 6.5 mLof H₂O. The resulting suspension was heated to reflux and 1 to 2 g ofH₂O was added to obtain a colorless solution. The solution was slowlycooled down to room temperature (over the course of 1 h) and stirred for3 h at room temperature. The suspension was filtered and the residue waswashed twice with acetone (10 mL). The product was dried under reducedpressure (50 mbar) at 60° C. to produce 4.9 g (48% yield) of product(ee>98.9).

Step 5: Conversion of Salt to FreeAmine—(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

The L-tartaric acid salt of8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (300 mg, 0.87mmol) was added to a 25 mL round bottom flask with 50% sodium hydroxidesolution (114 μL, 2.17 mmol) with an added 2 mL of water. The mixturewas stirred 3 minutes at room temperature. The solution was extractedwith methylene chloride (5 mL) twice. The combined organic extracts werewashed with water (5 mL) and evaporated to dryness on the pump to affordfree amine (220 mg crude weight). LC/MS 196 M+H).

Step 6: Preparation of(R)-N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride salt (1.0 g, 4.31 mmol) in dichloromethane (50 mL) at 0°C. was treated with pyridine (1.0 mL) and trifluoroacetic anhydride(1.35 g, 6.46 mmol). This was warmed to 20° C., stirred for 3 h anddiluted with 1M HCl (25 mL). This was extracted with dichloromethane(2×50 mL) and the organics dried with MgSO₄, filtered and concentratedto give 1.17 g as an off-white solid. ¹H NMR (400 MHz, CDCl₃, mixture ofrotamers) δ 7.27 (m, 1H), 6.96 (m, 1H), 4.26 (bm, 0.6H), 4.19-4.03 (m,1.7H), 3.92-3.87 (m, 0.8H), 3.75-3.69 (m, 0.8H), 3.47-3.22 (m, 2H), 2.91(m, 1H), 1.28-1.25 (m, 3H). MS calculated for C₁₃H₁₃ClF₃NO+H: 292,observed: 292.

Step 7: (R)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Compound,7 was prepared from(R)-N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineutilizing a similar two step procedure as described herein for thepreparation of Compound 5. ¹H NMR (400 MHz, CDCl₃) δ 7:40 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1 H), 4.17 (m, 1 H), 3.55 (m, 2 H), 3.5-3.3 (m, 2H), 3.2-3.0 (m, 2 H), 1.43 (d, J=7 Hz, 3 H). MS calculated forC₁₁H₁₃Cl₂N+H: 230, observed: 230.

Example 3.8 Preparation of(S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 8)

Step 1: Preparation of(S)-N-Trifluoroacetyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

A solution of(S)-N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(0.875 g, 3.0 mmol) in dichloroethane (7 mL) was treated withN-bromosuccinimide (0.284 g, 2.1 mmol) and trifluoromethansulfonic acid(0.639 g, 4.2 mmol). The reaction was stirred for 16 h at 75° C.,diluted with ethyl acetate (20 mL) and extracted with water (2×10 mL).The organics were dried with MgSO₄, filtered and concentrated. Flashchromatography (5% EtOAc in hexanes, silica) resulted in 0.13 g of aclear oil. MS calculated for C₁₃H₁₂BrClF₃NO+H: 370, observed: 370.

Step 2: Preparation of(S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

Compound 8 was prepared from(S)-N-trifluoroacetyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineutilizing a similar procedure as described herein for the preparation ofCompound 5.(S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasobtained from(S)-N-trifluoroacetyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H),3.92-3.87 (m, 1H), 3.29-3.20 (m, 2H), 3.11 (dd, J=14, 5 Hz, 1H), 2.99(dd, J=14, 2 Hz, 1H), 2.74-2.65 (m, 2H), 1.32 (d, J=7 Hz, 3H). MScalculated for C₁₁H₁₃BrClN+H: 274, observed: 274.

Example 3.9 Preparation of(R)-N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 9)

A solution of(R)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.05 g,0.20 mmol) in dichloroethane (3 mL) was treated with sodiumtriacetoxyborohydride (0.073 g, 0.35 mmol) and formaldehyde (0.017 mL,37% solution in water). This was stirred at 20° C. for 2 h. The reactionwas diluted with 15% NaOH and extracted with ethyl acetate (2×10 mL).The organics were dried with MgSO₄, filtered and concentrated to give0.042 g as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=8 Hz, 1H), 6.89(d, J=8 Hz, 1H), 3.91-3.88 (m, 1H), 3.28 (ddd, J=15, 12, 2 Hz, 1H),2.99-2.88 (m, 2H), 2.68 (ddd, J=15, 5, 1 Hz, 1H), 2.36-2.32 (m, 4H),2.13 (t, J=11 Hz, 1H), 1.27 (d, J=7 Hz, 3H). MS calculated forC₁₂H₁₅Cl₂N+H: 243, observed: 243.

Example 3.10 Preparation of(S)-N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 10)

Step 1: Preparation of(S)-N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

Compound 10 was prepared from(S)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizinga similar procedure as described herein for the preparation of Compound9. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H),3.91-3.88 (m, 1H), 3.28 (ddd, J=15, 12, 2 Hz, 1H), 2.99-2.88 (m, 2H),2.68 (ddd, J=15, 5, 1 Hz, 1H), 2.36-2.32 (m, 4H), 2.13 (t, J=11 Hz, 1H),1.27 (d, J=7 Hz, 3H). MS calculated for C₁₂H₁₅Cl₂N+H: 243, observed:243.

Example 3.11 Preparation of(S)-N-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Compound 11)

Compound 11 was prepared from(S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepineutilizing a similar procedure as described herein for the preparation ofCompound 9. ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J=8 Hz, 1H), 6.92 (d, J=8Hz, 1H), 3.94-3.88 (m, 1H), 3.29 (ddd, J=15, 12, 2 Hz, 1H), 2.98-2.93(m, 1H), 2.90 (ddd, J=15, 6, 1 Hz; 1H), 2.36-2.32 (m, 4H) 2.13 (t, J=11Hz, 1H), 1.33 (d, J=7 Hz, 3H). MS calculated for C₁₂H₁₅Cl₂N+H: 288,observed: 288.

Example 4

Separation of Enantiomers for Selected Compounds of the Invention

Compounds of the present invention can be separated into theirrespective enantiomers using a Varian ProStar HPLC system with a 20mm×250 mm Chiralcel OD chiral column, eluting with 0.2% diethylamine invarious concentrations of isopropanol (IPA) in hexanes, for example, 5%IPA in hexanes, 1% IPA in hexanes and like concentrations.

It is intended that each of the patents, applications, printedpublications, and other published documents mentioned or referred to inthis specification be herein incorporated by reference in theirentirety.

Those skilled in the art will appreciate that numerous changes andmodifications may be made to the preferred embodiments of the inventionand that such changes and modifications may be made without departingfrom the spirit of the invention. It is therefore intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound of Formula (I):

wherein: R₁ is H or C₁₋₈ alkyl; R₂ is C₁₋₄ alkyl, —CH₂—O—C₁₋₄ alkyl,C₁₋₄ haloalkyl or CH₂OH; and R₃, R₄, R₅ and R₆ are each independently H,C₁₋₄ alkyl, amino, cyano, halogen, C₁₋₄ haloalkyl, nitro or OH; or apharmaceutically acceptable salt, hydrate and solvate thereof; providedthat when R₂ is C₁₋₄ alkyl, —CH₂—O—C₁₋₄ alkyl, and CH₂OH then R₃ and R₆are not both hydrogen.
 2. The compound according to claim 1 wherein R₁is H.
 3. The compound according to claim 1 wherein R₁ is C₁₋₈ alkyl.4-8. (canceled)
 9. The compound according to claim 1 wherein R₂ is C₁₋₄alkyl.
 10. The compound according to claim 1 wherein R₂ is methyl.11-13. (canceled)
 14. The compound according to claim 1 wherein R₂ isC₁₋₄ haloalkyl.
 15. (canceled)
 16. The compound according to claim 1wherein R₃ is H.
 17. The compound according to claim 1 wherein R₃ isC₁₋₄ alkyl. 18-20. (canceled)
 21. The compound according to claim 1wherein R₃ is halogen. 22-25. (canceled)
 26. The compound according toclaim 1 wherein R₃ is C₁₋₄ haloalkyl. 27-29. (canceled)
 30. The compoundaccording to claim 1 wherein R₄ is H.
 31. The compound according toclaim 1 wherein R₄ is C₁₋₄ alkyl. 32-34. (canceled)
 35. The compoundaccording to claim 1 wherein R₄ is halogen. 36-39. (canceled)
 40. Thecompound according to claim 1 wherein R₄ is C₁₋₄ haloalkyl. 41-43.(canceled)
 44. The compound according to claim 1 wherein R₅ is H. 45.The compound according to claim 1 wherein R₅ is C₁₋₄ alkyl. 46-48.(canceled)
 49. The compound according to claim 1 wherein R₅ is halogen.50-53. (canceled)
 54. The compound according to claim 1 wherein R₅ isC₁₋₄ haloalkyl. 55-57. (canceled)
 58. The compound according to claim 1wherein R₆ is H.
 59. The compound according to claim 1 wherein R₆ isC₁₋₄ alkyl. 60-62. (canceled)
 63. The compound according to claim 1wherein R₆ is halogen. 64-67. (canceled)
 68. The compound according toclaim 1 wherein R₆ is C₁₋₄ haloalkyl. 69-71. (canceled)
 72. The compoundof claim 1 selected from the group consisting of:6,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;6-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine;8-Chloro-9-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and8,9-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
 73. Thecompound of claim 1 that is9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
 74. Thecompound of claim 1 selected from the group consisting of:N-methyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; andN-methyl-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.75. The compound according to claim 1 wherein said compound is an Renantiomer.
 76. The compound according to claim 1 wherein said compoundis an S enantiomer.
 77. A pharmaceutical composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.78. A method of modulating a 5HT_(2C) receptor comprising contactingsaid receptor with a therapeutically effective amount of a compoundaccording to claim
 1. 79. The method according to claim 78 wherein saidcompound is an agonist of said receptor.
 80. A method of prophylaxis ortreatment of disorders of the central nervous system; damage to thecentral nervous system; cardiovascular disorders; gastrointestinaldisorders; diabetes insipidus or sleep apnea comprising administering toan individual in need of such prophylaxis or treatment a therapeuticallyeffective amount of a compound according to claim 1 or a pharmaceuticalcomposition according to claim
 77. 81. The method according to claim 80wherein the disorders of the central nervous system are selected thegroup consisting of depression, atypical depression, bipolar disorders,anxiety disorders, obsessive-compulsive disorders, social phobias orpanic states, sleep disorders, sexual dysfunction, psychoses,schizophrenia, migraine and other conditions associated with cephalicpain or other pain, raised intracranial pressure, epilepsy, personalitydisorders, Alzheimer disease, age-related behavioral disorders,behavioral disorders associated with dementia, organic mental disorders,mental disorders in childhood, aggressivity, age-related memorydisorders, chronic fatigue syndrome, drug and alcohol addiction,obesity, bulimia, anorexia nervosa and premenstrual tension.
 82. Themethod according to claim 81 wherein the disorder of the central nervoussystem is obesity.
 83. (canceled)
 84. The method according to claim 81wherein the sexual dysfunction is Male erectile dysfunction. 85-89.(canceled)
 90. The method according to claim 82 or 84 wherein saidindividual is a human.
 91. A method of decreasing food intake of anindividual comprising administering to said individual a therapeuticallyeffective amount of a compound according to claim 1 or a pharmaceuticalcomposition according to claim
 77. 92. (canceled)
 93. The methodaccording to claim 91 wherein said individual is a human.
 94. A methodof inducing satiety in an individual comprising administering to saidindividual a therapeutically effective amount of a compound according toclaim 1 or a pharmaceutical composition according to claim
 77. 95.(canceled)
 96. The method according to claim 94 wherein said individualis a human.
 97. A method of controlling weight gain of an individualcomprising administering to said individual suffering from weightcontrol a therapeutically effective amount of a compound according toclaim 1 or a pharmaceutical composition according to claim
 77. 98.(canceled)
 99. The method according to claim 97 wherein said individualis a human. 100-103. (canceled)
 104. A method of producing apharmaceutical composition comprising admixing at least one compoundaccording to claim 1 and a pharmaceutically acceptable carrier. 105-123.(canceled)
 124. The compound according to claim 1 wherein: R₁ is H,methyl, ethyl, n-propyl, iso-propyl or n-butyl; R₂ is methyl, ethyl,iso-propyl, n-butyl or —CF₃; R₃ is H, —CH₃, amino, cyano, fluorine atom,chlorine atom, bromine atom, iodine atom, CF₃, nitro or —OH; R₄ is H,—CH₃, amino, cyano, fluorine atom, chlorine atom, bromine atom, iodineatom, CF₃, nitro or —OH; R₅ is H, —CH₃, amino, cyano, fluorine atom,chlorine atom, bromine atom, iodine atom, CF₃, nitro or —OH; and R₆ isH, —CH₃, amino, cyano, fluorine atom, chlorine atom, bromine atom,iodine atom, CF₃, nitro or —OH.
 125. A method of treating a 5HT_(2C)receptor associated disorder comprising administering to an individualin need of such treatment an effective amount of a compound according toclaim 1, or a pharmaceutical composition according to claim 77.